The long-term objective of this project is the development of genetic approaches to treat neurodegenerative diseases particularly Parkinsons disease and to elucidate pathogenetic mechanisms. In addition, basic transcription control studies are carried out for genes relevant to Parkinsons disease such as those encoding striatal dopamine receptors. In search for a novel and accessible source of progenitor cells to be used as vehicles for ex vivo gene transfer to the brain, we have been investigating the potential role of marrow stem cells. During FY99, we found that the normal process by which marrow progenitor cells seed the brain and differentiate into presumably different cell types including astrocytes is accelerated with brain injury. Thus, these cells home into regions of brain pathology preferentially making them even more selective vehicles for therapeutic gene transfer.Towards our studies about pathogenesis of neurodegenerative disorders, we have identified a novel protein PQBP1 that interacts with polyglutamine tracts of various molecules implicated in a number of disorders. Detailed functional analysis of PQBP1 is currently underway. In addition, since point mutations in the alpha-synuclein gene have been associated with autosomal dominant parkinsonism, we have studied the degradation of this neuronal protein and found it to be processed by the ubiquitin- proteasome pathway. Elucidation of this proteins fate could lead to understanding the pathogenesis of Parkinsons disease.Our transcription control studies revealed up-regulation of the D1A dopamine receptor gene by estrogen accounting for some of the motor manifestations in parkinsonian women with changes in this hormone level. We also found that the complex regulation of dopamine receptors in vivo by glucocorticoids is largely due to increased presynaptic dopamine release that secondarily alters postsynaptic function. In addition, we have characterized the murine D1A dopamine receptor gene promoter, created hybrid contstucts with selective neuronal expression which are being tested in in vivo animal models for their utility in neuronal selective gene transfer. - parkinson, gene transfer, alpha-synuclein, transcription, gene regulation, dopamine, receptor.